Pyrano pyridines and process for their production



United States Patent M PYRANO PYRIDINES AND PROCESS FOR THEIR PRODUCTIONMaximilian von Strandtmann, Rockaway Township, Marvin P. Cohen, NewMilford, and John Shavel, Jr., Mendham, N.J., assignors toWarner-Lambert Pharmaceutical Company, Morris Plains, NJ., a corporationof Delaware No Drawing. Filed June 28, 1966, Ser. No. 561,071

Int. Cl. C07d 99/04 U.S. Cl. 260-287 23 Claims ABSTRACT OF THEDISCLOSURE A class of pyrano pyridines of the formula:

I 5 wherein R is diaralkylamino, lower alkyl aryl amino, hydroxy,dilower alkylamino, etc.; R is hydrogen, lower alkyl, cycloalkyl, aryland aralkyl; R is hydrogen, lower alkyl, cycloalkyl, aryl and acyl; R ishydrogen, lower alkyl, cycloalkyl and aryl; and Z is the aromaticnucleus.

These compounds are prepared by reacting a compound of the formula:

file N or the enamine derivative thereof formed from an amine of theformula: V

with an amino alcohol compound of the formula:

These compounds are useful as psychotropic agents.

Patented Dec. 22, 1970 This invention relates to novel heterocycliccompounds and relates more particularly to pyrano pyridines of theformula:

wherein R represents diaralkylarnino, lower alkyl aryl amino, hydroxy,dilower alkylamino, pyrrolidino, morpholino, piperidino; R representshydrogen, lower alkyl, cycloalkyl, aryl and aralkyl; R representshydrogen, lower alkyl, cycloalkyl, aryl and acyl; R represents hydrogen,lower alkyl, cycloalkyl and aryl; Z represents an aromatic nucleus suchas benzene, pyridine, naphthalene, phenanthrene, isoquinoline andquinoline; and R represents hydrogen, halogen, nitro, lower alkoxy,amino, dialkylamino, acylamino, lower alkyl and aryl.

In the above definitions for R R R R and R the term lower alkylrepresents an alkyl group containing from 1 to -6 carbon atoms such asmethyl, ethyl, propyl, isopropyl, butyl, iso'butyl and the like. Theterm lower alkoxy includes an alkoxy group containing from 1 to 6 carbonatoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxyand the like. i

The aryl portion in the terms aryloxy, aralkoxy, aralkyl and aryincludes monocyclic as well as bicyclic aromatic nuclei such as phenyl,naphtho, isoquinolino and the like.

The term acyl is employed to designate a radical derived from acarboxylic acid.

The term aromatic nucleus includes compounds containing a homocyclicnucleus as well as compounds having a heterocyclic nucleus.

The term halogen includes the four halogens, i.e. chlorine, bromine,fluorine and iodine.

The symbols R R R R Z and R used hereinafter have the same meaning asdefined.

The present invention also includes within its scope novel processes forthe production of these compounds.

The compounds of this invention exhibit chlorpromazine-like activity andare useful in conditions whenever chlorpromazine is indicated. Thus, forexample, they are useful in mitigating conditions associated withemotional stress such as vomiting and hiccup.

Other compounds of this invention elicit imipraminelike central nervoussystem stimulations. These products may be used as antidepressantagents.

Doses of about 1 to mg. several times daily are generally recommended toproduce the desired central nervous system effects.

In use, the compounds of this invention may be combined with knownpharmaceutical diluents such as lactose, starch, dicalcium phosphate andthe like to form commonly employed dosage forms such as tablets orpills. They may also be dissolved in an isotonic solution suitable forparenteral injection.

Dosage forms known to the art such as sustained release tablets orliquids, capsules, suppositories and the like may also be preparedaccording to procedures known in the pharmaceutical art.

The compounds of this invention may be prepared by a number ofprocedures as follows:

PROCEDURE A In accordance with this procedure a compound of thestructure:

is heated with an equivalent amount of a compound of the structure IIIin dioxane at a temperature of from about 70 to 95 C. until no compoundof the formula is detectable which is formed as a byproduct of thereaction. At this point, water is added and the mixture is then heatedat a temperature of about 90 to 98 C. for an additional period such as60 to 70 minutes. The addition of water is omitted in the case when R inthe final product is an amine, i.e. dilower alkylamine, pyrrolidine,morpholine or piperidine. Compound of structure 111 may be used also inthe form of its quaternary salt or the N-oxide derivatives.

The choice of solvent is nonessential and the reaction can be carriedout in many other inert organic solvents such as toluene, xylene and thelike.

The reaction which takes place during Procedure A is quite unexpectedbecause it is generally known that phenolic Mannich bases of structureIII above cannot be expected to alkylate compounds containing reactivemethylene or methylidene groups such as in structure II above, becauseof their strong tendency towards dimerization. See for example H.Hellmann and G. Opitz, a- Aminoalkylierung, Verlag Chemie G.m.b.H.,Weinheim (1960), page 284; and F. Poppelsdorf and J. Holt, 1. Chem.Soc., 1954, 4094.

PROCEDURE B Procedure B involves the reaction of a compound of thestructure IV:

II iv with a compound of the structure III above utilizing the samereaction conditions as described for Procedure A except that the stepinvolving heating with Water is entirely omitted.

Procedure B is limited to those cases where the final product R does notinclude an amine.

PROCEDURE C Procedure C is analogous to Procedure B except that nosolvent is used and in addition the reaction is carried out at Thesymbols R R R and R used in the above description, represent hydrogen,lower alkyl, aralkyl or aryl or taken together with nitrogen to whichthey are attached form a ring system such as piperidine, morpholine orpyrrolidine. The reaction products obtained in each of theabove-described processes are worked up and recovered in accordance withprocedures well known to the art.

The Mannich bases III used as the starting material are prepared bystandard methods described in oz-Aminoalkylierung by H. Hellmann and G.Opitz, Verlag Chemie G.m.b.H., Weinheim, 1960.

The enamines II used as the starting materials are prepared by standardmethods according to G. Stork et al. (J. Am. Chem. Soc., 85, 207 (1963))from amines such as dialkylamines, pyrrolidine, morpholine, piperidineand the like and from piperidine derivatives (compound IV).

The following examples are included in order further to illustrate theinvention.

All temperatures referred to in these examples are given in degreescentigrade.

EXAMPLE 1 EXAMPLE 2 10-benzoyl-8,9,10,11,11a,12-l1exahydro-7aH-pyrido-[3 ,4' 5,6] pyrano 3,2-f] quinolin-7a-ol A solution of 14.9 g. ofN-benzoyl-4-piperidone and 10 g. of pyrrolidine in 250 ml. of benzene isrefluxed through a Dean-Stark trap for hours. The benzene and excesspyrrolidine are removed in vacuo and the residual gum is dissolved in 70ml. of dioxane. The solution is treated with 14.7 g. ofS-dimethylaminoethyl-6-quino1inol and refluxed for 4 days. Afteraddition of 14 ml. of water, the mixture is refluxed for 2 hours andconcentrated to a heavy gum in vacuo. The gum is recrystallized fromethanol, M.P. 249-52; yield: 16 g. (89%); m (e) 240 (48,400); v 710(m.), 825 (m.), 905 (ms.), 960 (ms.), 1075 (m.), 1150 (m.), 1225 (ms.),1505 (m.), 1635 (s.), 3100 (m.) cm.-

Analysis.Calcd. for C H N O (percent): C, 73.31; H, 5.59; N, 7.77. Found(percent): C, 73.31; H, 5.72; N, 7.70.

'EXAMPLE 3 -benzyl-8,9,10,11,11a,12-hexahydro-7aH-naphtho- [1,2' 5,6]pyrano 3,2-c] pyridin-7a-ol A solution of 10 g. of1-dimethylaminomethyI-Z-naphthol and 9 g. of 1-benzyl-4-piperidone in 50ml. of dioxane is refluxed for 4 days. The solvent is removed in vacuo,and the residual gum dissolved in ethyl acetate and chromatographed on acolumn of 350 g. of Florisil, with ethyl acetate development. Thefractions which are homogenous on thin layer chromatography are combinedand evaporated to dryness. The residue is dissolved in absolute ethanoland treated with ethanolic HCl. The crystalline hydrochloride isfiltered off and dissolved in water. The solution is made basic with 40%KOH. The precipitated base is filtered and recrystallized fromacetonitrile to yield 10-benzyl-8,9,10,1 1,11a,12-hexahydro-7aH-naphtho- [1,2:5,6]pyrano [3,2 c]pyridin 7a ol, M.P.137.5- 139.5; A ma (6) 231 (89,800), 266 (5100), 277 (5800), 288 4300317 2400 331 (2600); u 690 (m.), 735 (ms.), 810 (ms.), 970 (m.), 1020(m.), 1175 (m.), 1225 (m.), 1595 (mw.), 1620 (mw.) cm.-

Analysis.'Calcd. for C H N-O (percent): C, 79.97; H, 6.71; N, 4.06.Found (percent): C, 79.68; H, 6.68; N, 4.31.

EXAMPLE 4 10-benzoyl-8,9,10, 1 1 a, 12-hexahydro-7aH-naphtho- [1,2' 5,6]pyrano [3,2-c] pyridin-7aH-ol A solution of 10.15 g. ofN-benzoy1-4-piperidone, and 7.1 g. of pyrrolidine in 250 ml. of benzeneis refluxed through a Dean-Stark trap for 5 hrs. The benzene and excesspyrrolidine are evaporated in vacuo and the residual gum is taken up in50 ml. of dioxane. The solution is treated with 10.05 g. ofl-dimethylaminomethyl-Z- naphthol, refluxed for 6 days, treated with 10ml. of water, and refluxed for 2 hrs. The solvents are removed in vacuo,and the residual gum is dissolved in ethyl acetate. The solution ischromatographed on a column of 400 g. of activated magnesium silicatesuch as Florisil with ethyl acetate development. The fractions whichcrystallize are combined and recrystallized from absolute ethanol toyield 10 benzoyl 8,9,10,11a,12 hexahydro-7aH-naphtho[1,2':5,6]pyranol[3,2-c]pyridin 7aH-ol, M.P. 192-194"; A m, (e)23 1 (86,800), 265 (6,000), 275 (6,000), 287 (4,800), 316 2,200 3312,700); 11 690 (ms.), 735 (ms.), 815 (ms.), 960 (ms.), 1035 (s.), 1160(m.), 1230 (ms.), 1280 (ms.), 1500 (m.), 1600 (s.), 1610 (s.), 3275(ms.) cm.-

Analysis.-Calcd. for C H NO (percent): C, 76.86; H, 5.89; N, 3.90. Found(percent): C, 77.12; H, 5.98; N, 3.75.

EXAMPLE 5 9-benzoyl-7a,8,9,10,1 1,1 1a-hexahydro-7H-pyrido- [3,4 5,6]pyrano[3,2-h] quinolin l la-ol O OH A solution of 10.15 g. ofN-benzoyl-4-piperidone and 7.1 g. of pyrrolidine in 250 ml. of benzeneis refluxed through a Dean-Stark water separator for 5 hrs. The benzeneand excess pyrrolidine are removed in vacuo, and the gummy residue wasdissolved in ml. of dioxane. 7-dimethylaminomethyl-S-quinolinol (10.1g.) is added, and the mixture is refluxed for 4 days, treated with 10ml. of H 0, refluxed for 2 hrs. and evaporated in vacuo, The residualgum is dissolved in ethyl acetate, and chromatographed on 300 g. ofactivated magnesium silicate,

with ethyl acetate development. The fractions which EXAMPLE '67,7a,8,9,10,11-hexahydro-9,1 l-dimethyl-l laH-naphtho- [2,1 5,6]pyrano[3,2-c] pyridine-lla-ol H 0 CH3 NCHa This compound is prepared inanalogous fashion to 7,7a,8,9,10,11 -hexahydro 9 methyl-11aH-naphtho[2',1:5,6]pyrano[3,2-c]pyridin 1121-01 from 12 g. of2-dimethylaminomethyl-l-naphthol-HC1, and 9 g. of pyrrolidine enamine of1,3-dimethyl-4-piperidone. The obtained material is recrystallized fromacetonitrile, M.P. 179; A m (e) 213 (40,300), 235 (41,000), 292 (4800),310 (3300), 323 (3000); v 745 (ms.), 810

. 7 (m.), 970 (s.), 1060 (s.), 1080 (vs.), 1150 (ms.), 1220 (m.), 1580(m.), 1600 (mW.), cmf

AnaIysis.-Calcd. for C H NO (percent): C, 76.29; H, 7.47; N, 4.94. Found(percent): C, 76.12; H, 7.50; N, 5.21.

' EXAMPLE 7 A solution of 20 g. of 2 dimethylaminomethyl-lnaphthol-HClin 30 ml. of H is made basic with conc. NH OH. The precipitated oil isextracted With four 25 ml. portions of chloroform; the combined extractsare dried over Na SO and concentrated to a heavy oil in vacuo. This oilis taken up in 50 ml. of dioxane and combined with 14 g. of pyrrolidineenamine of N-methyl-4- piperidone. The mixture is refluxed for 4 hrs.under a stream of nitrogen, treated with m1. of H 0, refluxed oneadditional hour, and evaporated in vacuo. The residue is recrystallizedfrom methanol with the aid of charcoal to yield 7,7 a,8,9,10, 11-hexahydro-9-methyl-1 laH-naphtho-[2',1':5,6]pyrano[3,2-c1pyridin-11a-ol, M.P. 192195, k my. (6) 213(42,200), 234 (42,200), 291 (5,100), 309 (3600), 324 (3100); v 740(ms.), 805 (s.), 920 (s.), 1075 (s.), 1140 (ms.), 1260 (ms.), 1580 (m.),1600 (mw.) cmf Analysis.Calcd. for C H NO (percent): C, 75.81; H, 7.11;N, 5.20. Found (percent): C, 76.08; H, 7.20; N, 5.39.

EXAMPLE 8 8,9,10,11,11a,12-hexahydro-10-methyl 12phenyl-7a(lpyrrolidinyl) 7aH naphtho[1,2':5,6]pyran0[3,2-c]

A solution of 13.5 g. of 1-(a-dimethylaminobenzyl)-2- naphthol, and 8.3g. of pyrrolidine enamine of N-methyl- 4-piperidone in ml. of dioxane isrefluxed under a stream of nitrogen for 4.5 hrs. The solvent is removedin vacuo, and the residual gum is crystallized from ethyl acetate toyield 8,9,10,11,11a,12-hexahydro-10-methyl- 12 phenyl-7a(l-pyrrolidinyl)7aH naphtho[1',2':5,6] pyrano[3,2-c]pyridine; M.P. 203207; k m (e) 234(67,000), 266 (5000), 277 (5700), 289 (4100), 317 (2300), 331 (3000); v700 (ms.), 750 (ms.), 810 (ms.), 915 (ms.), 1000 (ms.), 1225 (s.), 1605(m.), 1625 (m.) cmf Analysis.-Calcd. for C H N O (percent): C, 81.37; H,7.59; N, 7.03. Found (percent): C, 81.31; H, 7.55; N. 6.99.

8 EXAMPLE 9A 8,9,10,11,11a,12 hexahydro-8,10-dimethyl-7aH-naphtho-[1,2:5,6]pyrano[3,2-c]pyridin-7a-ol prepared by Procedure A A solutionof 8.9 g. of 1-dimethylaminomethy1-2- naphthol, and 8 g. of pyrrolidineenamine of 1,3-dimethyl- 4-piperidone in 25 ml. of dioxane is refluxedunder a stream of nitrogen for 4.5 hrs. The solution is then treatedwith 5 ml. of H 0, refluxed for one additional hour and concentrated invacuo. The residual gum is crystallized from EtOH to yield 8,9,l0,ll,lla,l2-hexahydro8,10-dimethyl7aH-naphtho[1',2':5,6]pyrano[3,2-c]pyridin-7ao1, M.P. 164170.

EXAMPLE 9B 8,9,l0,11,11a,12-hexahydro-8,10-dimethyl-7aH naphtho-[1,2:5,6]pyrano[3,2-c1pyridin-7a-ol prepared by Procedure B A solutionof 8.2 g. of 1,3-dimethyl-4-piperidone HCl in 20 ml. of H 0 is madebasic with 40% NaOH. The precipitated oil is extracted four times with25 ml. portions of chloroform. The combined extracts are dried over NaSO and concentrated to an oil in vacuo. The oil is dissolved in 50 ml.of dioxane; the solution is treated with 10 g. of1-dimethylaminomethyl-Z-naphthol and refluxed for one week. The solventis removed in vacuo and the gummy residue is recrystallized fromacetonitrile to give 8,9,l0,1l,1la,12 hexahydro-8,l0-dimethyl-7aH-naphtho[1,2:5,6]pyrano[3,2-c]pyridin-7a-ol, M.P. 165 167; x m r (e) 231(80,000), 277 (5,100), 288 (4,000), 317 (2,000), 331 (2,400); v 750(ms.), 770 (ms.), 805 (s.), 890 (m.), 910 (ms.), 925 (ms.), 1010 (ms.),1055 (ms.), 1115 (ms.), 1150 (ms.), 1220 (ms.), 1510 (m.), 1595 (m.),1620 (m.) cm.-

Analysis.Calcd. for C H NO (percent): C, 76.29; H, 7.47; N, 4.94. Found(percent): C, 76.37; H, 7.36; N, 4.78.

EXAMPLE 10 1,2,3,4,10,10a-hexahydro-2-methy1-4aH 1] benzopyrano 3,2-c]pyridin-4a-ol A solution of 7.55 g. of o-dimethylaminomethylphenol and8.3 g. of pyrrolidine enamine of N-methyl-4-piperidone in 50 ml. ofdioxane is refluxed for 2 weeks. The solution is treated with 10 ml. ofH 0, and refluxed for 2 hrs. The solvents are removed in vacuo and thegummy residue is recrystallized from acetonitrile to give 1,2,3,4,10,10a hexahydro 2 methyl 4aH [1]benzopyrano [3,2-c]pyridin-4a-ol, M.P.144-46; A m (6) 214 (78,300), 273 (21,200), 279 (21,000); p 750 (m.s),805 (m.), 930 (ms.), 970 (m.), 1050 (ms.), 1140 (s.), 1220 (s.), 1250(ms.), 1585 (ms.), 1610 (mw.),cm."

9 Analysis.Calcd. for C13H17N02 (percent): C, 71.20; H, 7.82; N, 6.39.Found (percent): C, 71.32; H, 7.82; N, 6.22.

EXAMPLE 11 8,9,10,11,1 1a,12-hexahydro-10-methy1-7aH- pyrido 3,4' 5 ,6]pyrano 3,2-f quinolin-7a-o1 A solution of 5 g. ofS-dimethylaminomethyl-6-quinolinol and 4.1 g. of pyrrolidine enamine ofN-methyl-4-piperidone in 25 ml. of dioxane is refluxed for 3 days. Thesolution is treated With 5 ml. of H 0, refluxed 2 hrs. and evaporated invacuo. The gummy residue is recrystallized from ethyl acetate, M.P.16466, to yield 8,9,10,11,11a, 12 hexahydro 10 methyl 7aH pyrido[3,4':5,6] pyrano[3,2-f]quinolin-7a-ol; A m (e) 240 (45,000), 285(3200), 325 (3520); 11 810 (ms.), 935 (ms.), 960 (ms.), 1020 (s.), 1140(ms.), 1230 (ms.), 1510 (m.), 1,595 (m.),1615 (m.), 3100 (ms.) cmfAnalysis.Calcd. for C H N O (percent): C, 71.09; H, 6.71; N, 10.36.Found (percent): C, 71.11; H, 6.69; N, 10.35.

EXAMPLE 12 3 -bromo-8,9,10,11,11a,12-hexahydro-8,10-dimethyl-7aH-naphtho 1,2 5 ,6] pyrano [3 ,2-c]

pyridin-7a-ol I on C Ha

This compound is prepared by the same method as 8,9,10,11,11a,12hexahydro 1O methyl 7aH-naphtho [1',2:5,6]pyrano[3,2-c]pyridin-7a-olfrom 14 g. of 6- bromo-1-dimethylaminomethyl-2-naphthol, and 6.35 g. of1,3-dimethyl-4-piperidone. The product is recrystallized from absoluteethanol, M.P. 205-207; x m (2) 237 (72,000), 269 (5,600), 279 (6,000),290 (3,900), 326 (2,000 341 2,300); u 780 (m.), 815 (ms.), 880 (ms.),910 (ms.), 925 (ms.), 1000 (ms.), 1055 (ms.), 1150 (ms.), 1260 (ms.),1590 (m.), 1620 (m.) CIIII'I.

Analysis.Calcd. for C H BrNO (percent): C, 59.68; H, 5.56; N, 3.87.Found (percent): C, 59.93; H, 5.60; N, 4.14.

10 EXAMPLE 13 3-br0mo-8,9,10,11,1 1a,12-hexahydro-10-methyl-7aH-naphtho[ 1',2 5 ,6] pyrano [3,2-c] pyridin-7a-ol This compound isprepared by the same method as 8,9, 10,11,11a,12 hexahydro 10 methyl 7aHnaphtho [1',2':5,6]pyrano[3,2-c]pyridin-7a-ol, from 12 g. of 6-bromo-1-dimethylaminomethy1-2-naphtho1, and 4.85 g. of1-methyl-4-piperidone. The product is recrystallized from absoluteethanol, M.P. 207-209"; x m (6) 237 (72,700), 269 (5,600), 280 (6,000),290 (3,800), 325 (2,100), 340 (2,300); v 750 (m.), 802 (s.), 875 (ms.),980 (ms.), 1025 (s.), 1135 (m.), 1230 (s.), 1590 (m.), 1615 (mw.) cmrAnalysis.-Calcd. for C H BrNO C, 58.63; H, 5.21; N, 4.02. Found(percent): C, 58.67; H, 5.29; N, 3.92.

EXAMPLE 14 8-benzoyl-6,7, 8,9,9a,10-hexah'ydro-5aH-pyrano [3,2-b5,6-c]dipyridin-5a-0l A solution of 30.3 g. of N-benzoyl-4-piperidoneand 21.3 g. of pyrrolidine in 750 ml. of benzene is refluxed for 5 hrs.through a Dean-Stark water trap. The benzene and excess pyrrolidine areremoved in vacuo and the residual gum is redissolved in ml. of dioxane.The solution is treated with 22.8 g. ofZ-(dimethylaminomethyl)-3-hydroxypyridine and refluxed for 13 days. Themixture is treated with 30 ml. of H 0 and refluxed for 2 hrs. Removal ofsolvents in vacuo leaves a gummy residue which is recrystallized fromabsolute ethanol to yield 8-benzoyl 6,7,8,9,9a,10 hexahydro-SaH-pyrano[3,2-b:5,6-c]dipyridin-5a-o1; M.P. 176-178"; A m (e) 279 (6,700); v 705(m.), 805 (m.), 955 (ms.), 1030 (m.), 1100 (m.), 1275 (ms.), 1600 (mw.),1625 (s.) cmf Analysis.-Calcd. for C H N O (percent): C, 69.66; H, 5.85;N, 9.03. Found (percent): C, 69.39; H, 5.70; N, 9.26.

EXAMPLE 15 1,2,3 ,4,10,10a-hexahydro-Z-methyl-8-phenyl-4aH[1]benzopyrano 3,2-c] pyridin-4a-ol A solution of 5.65 g. ofa-dimethylamino-4-phenyl-ocresol, and 4.15 g. of pyrrolidine enamine ofN-methyl-4- piperidone in 25 ml. of dioxane is refluxed 18 hrs. under astream of nitrogen. The solution is treated with ml. of H 0, andrefluxed 1 hr. more. The solvents are then removed in vacuo and theresidue recrystallized from abs. EtOH to yield 1,2,3,4,10,10ahexahyclro-2-methyl-8- phenyl-4aH[1]benzopyrano[3,2-c]pyridin 4a o1;M.P. 181-183; A m (e) 261 (19,000 v 690 (ms.), 755 (ms.), 830 (ms.), 965(ms.), 1025 (ms.), 1150 (m.), 1230 (ms) cmr' Analysis.Calcd. for C H NO(percent): C, 77.26; H, 7.17; N, 4.74. Found (percent): C, 77.16; H,7.16; N, 4.87.

EXAMPLE 16 8,9,10,1 1,1 1a,12-hexahydro-10-methyl-12-phenyl-7aH- naphtho1',2 5 ,6] pyrano 3,2-c] pyridin-7a-ol H @Afi (IJHB A solution of 4 g.of 8,9,10,11,11a,12-hexahydro-10- methyl 12 phenyl-7a-(l-pyrrolidinyl7aH naphtho- [1',2':5,6]pyrano[3,2-c1pyridine in ml. of dioxane and ml.of 1 N HCl is refluxed for 18 hrs. The solution is then made basic inthe cold with 10% NaOH solution and the precipitated product filtered,washed with cold H 0, and recrystallized from abs. EtOH to yield 8,9,10,11,11a,12 hexahydro 10 methyl 12 phenyl-7aH-naphtho[1',2':5,6]pyrano[3,2-c]pyridin-7a-ol; M.P. 192- 195; r m (e) 232(83,500), 266 (5900), 276 (7100), 288 (6000), 316 (3000), 330 (3500); v695 (ms.), 745 (ms.), 815 (s.), 960 (ms.), 1020 (ms.), 1145 (ms.), 1230(ms.), 1595 (mW.), 1620 (mw.) cmr Analysis.Calcd. for C H NO (percent):C, 79.97; H, 6.71; N, 4.06. Found (percent): C, 79.90; H, 6.96; N, 4.06.

EXAMPLE 17 7,7a,8,9, 10,1 1-hexahydro-9-methyl-1laH-pyrido [3,4' 5 ,6]pyrano 3,2-h] quinolin-l la-ol NCH A solution of 10.1 g. of7-dimethylaminomethyl-8- quinolinol and 5.6 g. of N-methyl-4-piperidonein ml. of dioxane is refluxed for 1 wk. The solvent is removed in vacuoand the residual gum dissolved in ethyl acetate and chromatographed on acolumn of 400 g. of florisil, with ethyl acetate development. Thefractions which crystallize on concentration are combined andrecrystallized from ethyl acetate to yield 7,7a,8,9,10,11-hexahydro-9-methyl 11aH pyrido[3',4:5,6]pyrano[3,2-h]quinolin- 11a-ol; M.P. 120123;i m, (e) 245 (45,100), 308 (3000); v 665 (m.), 790 (ms.), 830 (ms.), 925(ms.), 1080 (s.), 1140 (ms.), 1215 (m.), 1505 (ms.), 1620 (mw.) CH1."1.

Analysis.Calcd. for C, H N O (percent): C, 71.09; H, 6.71; N, 10.36.Found (percent): C, 71.31; H, 6.81; N, 10.34.

OH O A solution of 7.6 g. of 2-dimethylaminomethyl-3- hydroxypyridine,and 8.3 g. of pyrrolidine enamine of N-methyl-4-piperidone in 50 ml. ofdioxane is refluxed for 2 weeks. The solution is treated with 10 ml. ofwater, refluxed for 2 hrs. and evaporated in vacuo. The residual gum isrecrystallized from acetonitrile to yield 6,7,8,9,9a, 10 hexahydro 8methyl 5aH pyrauo[3,2-b:5,6-c] dipyridin-Sa-ol, M.P. 157-595; A mp. (e)219 (6,000), 280 (5,920); r/ 800 (ms.), 995 (s.), 975 (ms.), 1025 (s.),1105 (ms.), 1190 (ms.), 1215 (s.), 1250 (s.), 1580 (mw.), 1590(mw.) cm.-

Analysis.Calcd. for C H N O (percent): C, 65.43; H, 7.32; N, 12.72.Found (percent): C, 65.71; H, 7.44; N, 12.96.

EXAMPLE 19 8,9,10,1 1,11a,12-hexahydro-10-rnethyl-7a-(l-pyrrolidinyl-7aH-naphtho 1',2 5,6] pyrano [3 ,2-c] pyridine T) f L The solution of 5g. of l-dimethylaminomethyl-Z- naphthol, and 4.15 g. of pyrrolidineenamine of l-methyl- 4-piperid0ne in 25 ml. of dioxane was refluxed for3 hrs. under a stream of nitrogen. The solvent was removed in vacuo andthe residual gum was recrystallized from Skelly B, to yield8,9,10,11,11a,12-hexahydro-10-methy1-7a-(1- pyrrolidinyl) 7aHnaphtho[1',2':5,6]pyrano[3,2 c] pyridine; M.P. 101-05; A m (6) 231(78,000), 266 (4000), 277 (4900), 288 (3900), 317 (2000), 331 (2500); v750 (m.), 805 (s.), 880 (m.), 935 (m.), 980 (ms.), 1005 (ms.), 1150(m.), 1235 (ms.), 1595 (m.), 1625 (m.) cm.-

Analysis.-Calcd. for C H N O (percent): C, 78.22; H, 8.13; N, 8.69.Found (percent): C, 78.42; H, 8.21; N, 8.74.

EXAMPLE 20 1,2,3 ,4,10,10a-hexahydro-2,4-dimethyl-8-pheny1-4aH[1]-benzopyrano [3,2-c] pyridin-4a-ol This was prepared from 11.35 g. ofa-dimethylamino-4- phenyl-o-cresol and 9 g. of pyrrolidine enamine of1,3- dimethyl-4-piperidone in analogous fashion to 1,2,3,4,10,10a-hexahydro-2-methy1 8 phenyl 4aH[1]benzopyrano [3,2-c]pyridin-4a-ol.Recrystallized from acetonitrile, to yield 1,2,3,4,10,10a hexahydro 2,4dimethyl-8-phenyl- 4aH[1]benzopyrano[3,2-c]pyridin-4a-ol; M.P. 163.5-66; A m (e) 262 (19,300); u 690 (s.), 755 (s.), 820 (s.), 975 (s.), 1045(s.), 1135 (ms.), 1230,(s.), 1585 (mw.), 1600 (mw.), 1615 (mw.) cmr3,549,641 15 16 23. Process for the production of a compound of the withan equivalent amount of a compound of the formula: formula:

R CH a z a 3 n n whereln R 1s hydroxy or pyrrolldlno; R 18 hydrogen, 3 t9 alkyl of 1 to 6 carbon atoms' R is hydrogen alkyl of 1 r h rein R R Rand R each re resents lower alk l, to 6 carbon atoms benzoyl and benzyl;R4 18 hydrogen or be n l lovt er a lk l hen l or taken to ether with the1 1 iphenyl Z is benzo pyrido naphtho phenanthro quinolo p y p y g orisoquinolo R is Halogen phenyl which com trogen atom to WhlCh they areattached form a piperidlno,

5 morpholino or pyrrolldrno nucleus; at a temperature of pnses heating aCompound of the formula' about 70 to 90 C. until no basic fumes areformed, adding water to the reaction mixture and continue heating atabout 80 to 90 C. for about 60 to 70 minutes.

References Cited Chem. Abstracts, vol. 63, 1965, 18059 d, e, f, and grelied on.

N ALEX MAZEL,Primary Examiner A. M. T. TIGHE, Assistant Examiner U.S.Cl. X.R.

